These studies are designed to extend our information about the circadian control of normal hard tissue metabolism in growing animals, and to gain insight about the long term consequences of pharmacologic intervention at different clock hours. Preliminary data in rats suggested that the pace of chondrocyte proliferation and cartilage formation fracture callus maturation and bone allograft esteoinductive success was variable in a 24 hr. day - and that these phenomena could be modified selectively by corticosteroid treatment at only certain clock hours. Post-fracture linear bone growth was greatest after one month when trauma occurred at 1600 hrs. Our major objectives are now to explore the variations in chronoresponsivity of bone cells and chondrocytes in laboratory animals to metabolic stressors such as (1) endocrine agents, (2) fracture, (3) antigenic stimuli - adjuvant induced arthritis (AIA) in rats and the use of calcified and decalcified bone allografts to heal experimental long bone defects - and to demonstrate (4) how chronotherapeutic regimens with anabolic hormone and EHDP might reduce the severity of post-immobilization osteopenia. In each of these categories, rats, mice or rabbits will be entrained to a 12/12 hr. light-dark cycle for 2 weeks prior to study, and different groups will be treated at intervals of 4 hrs. in a total 24 hr. period to study the effects of endocrine chronotherapy and antigenic stimulation. Cartilage and bone matrix formation (collagen, hexosamine) will be studied radioisotopically. The effects of PGEl, penicillamine and dexamethasone chronotherapy will be test in AIA, and tetracycline (UV microfluoroescence) and radiostrontium Sr85 will be used to study the pace of bone formation and turnover. The etiology for the clock hour differences in the osteoinductive allograft response will be tested by immunologic techniques designed to measure possible differences in the production of enhancing antibodies.